Resistance to anticancer drugs is a problem in the treatment of pancreatic ductal carcinoma (PDAC) and overcoming it is an important issue. Recently, it has been reported that statins induce apoptosis in cancer cells but the mechanism has not been completely elucidated. We investigated the antitumor mechanisms of statins against PDAC and their impact on resistance to gemcitabine (GEM). Lovastatin (LOVA) increased mitochondrial oxidative stress in PDAC cells, leading to apoptosis. LOVA reduced lipid rafts in the plasma membrane and mitochondria, suppressed the activation of epithelial growth factor receptor (EGFR) and AKT in plasma membrane rafts, and reduced B-cell lymphoma 2 (BCL2)-Bcl-2-associated X protein (BAX) binding and the translocation of F1F0 ATPase in mitochondrial rafts. In the three GEM-resistant cell lines derived from MIA and PANC1, the lipid rafts in the cell membrane and the mitochondria were increased to activate EGFR and AKT and to increase BCL2-BAX binding, which suppressed apoptosis. LOVA abrogated these anti-apoptotic effects by reducing the rafts in the resistant cells. By treating the resistant cells with LOVA, GEM sensitivity improved to the level of the parental cells. Therefore, cholesterol rafts contribute to drug resistance in PDAC. Further clinical research is warranted on overcoming anticancer drug resistance by statin-mediated intracellular cholesterol regulation.

We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.

Pancreatic ductal adenocarcinoma (PDAC) one of the deadliest malignant tumor. Despite considerable progress in pancreatic cancer treatment in the past 10 years, PDAC mortality has shown no appreciable change, and systemic therapies for PDAC generally lack efficacy. Thus, developing biomarkers for treatment guidance is urgently required. This review focuses on pancreatic tumor organoids (PTOs), which can mimic the characteristics of the original tumor in vitro. As a powerful tool with several applications, PTOs represent a new strategy for targeted therapy in pancreatic cancer and contribute to the advancement of the field of personalized medicine.

Primary pancreatic squamous cell carcinoma is sporadic. The diagnosis is usually made following surgery or needle biopsy and requires a thorough workup to exclude metastatic squamous cell carcinoma. Squamous cell carcinoma of the pancreas often has a very poor prognosis. There is no treatment guideline for this type of cancer, and to date, no therapeutic regimen has been proven effective. Here, we report the effectiveness of immunotherapy in combination with chemotherapy against locally advanced squamous cell carcinoma of the pancreas with high programmed cell death ligand 1 (PD-L1) expression. Regional intra-arterial infusion chemotherapy consisting of nab-Paclitaxel followed by gemcitabine infused via gastroduodenal artery every three weeks for two cycles. This therapy resulted in the depletion of carcinoma, and the patient continues to lead a high-quality life with no symptoms for more than 16 months.

UNASSIGNED: To investigate the use of proton pump inhibitors (PPIs) and the risk of pancreatic cancer.
UNASSIGNED: A nested case-control analysis was conducted. Patients with pancreas cancer were matched with controls by propensity score. Univariate and multivariate logistic regression models were used to determine whether PPIs use affected the risk of pancreas cancer. Dose effect was analyzed based on the cumulative defined daily dose (DDD), which was calculated using the total supply of PPIs to individual patients in terms of days and quantity.
UNASSIGNED: A total of 1087 patients with pancreas cancer were matched with 1087 control patients from the database. The overall adjusted odds ratio (OR) of PPI use associated with pancreas cancer was 1.69 (95% confidence interval [CI], 1.44-2.05). Dose analysis by cumulative DDD, based on all types of PPI combined, revealed a lower adjusted OR of 0.92 (95% CI, 0.64-1.33) for those on <30 cumulative DDD compared with those on ≥150 cumulative DDD, whose adjusted OR was 2.19 (95% CI, 1.68-2.85). Compared with PPI nonusers, the risks of pancreas cancer were: OR 0.89 (95% CI, 0.62-1.27) for patients using PPI <30 days and 2.22 (95% CI, 1.68-2.94) for ≥150 days.
UNASSIGNED: Risk of pancreas cancer was associated with PPI use in patients with peptic ulcer diseases or gastroesophageal reflux disease.

OBJECTIVE: We investigated the value of CT texture analysis (CTTA) in predicting prognosis of unresectable pancreatic cancer.
METHODS: Sixty patients with unresectable pancreatic cancers at presentation were enrolled for post-processing with CTTA using commercially available software (TexRAD Ltd, Cambridge, UK). The largest cross-section of the tumour on axial CT was chosen to draw a region-of-interest. CTTA parameters (mean value of positive pixels (MPP), kurtosis, entropy, skewness), arterial and venous invasion, metastatic disease and tumour size were correlated with overall and progression-free survivals.
RESULTS: The median overall and progression-free survivals of cohort were 13.3 and 7.8 months, respectively. On multivariate Cox proportional hazard regression analysis, presence of metastatic disease at presentation had the highest association with overall survival (p = 0.003-0.05) and progression-free survival (p < 0.001 to p = 0.004). MPP at medium spatial filter was significantly associated with poor overall survival (p = 0.04). On Kaplan-Meier survival analysis of CTTA parameters at medium spatial filter, MPP of more than 31.625 and kurtosis of more than 0.565 had significantly worse overall survival (p = 0.036 and 0.028, respectively).
CONCLUSIONS: CTTA features were significantly associated with overall survival in pancreas cancer, particularly in patients with non-metastatic, locally advanced disease.
CONCLUSIONS: • CT texture analysis is easy to perform on contrast-enhanced CT. • CT texture analysis can determine prognosis in patients with unresectable pancreas cancer. • The best predictors of poor prognosis were high kurtosis and MPP.

Oxythiamine (OT), an analogue of anti-metabolite, can suppress the nonoxidative synthesis of ribose and induce cell apoptosis by causing a G1 phase arrest in vitro and in vivo. However, the molecular mechanism remains unclear yet. In the present study, a quantitative proteomic analysis using the modified SILAC method (mSILAC) was performed to determine the effect of metabolic inhibition on dynamic changes of protein expression in MIA PaCa-2 cancer cells treated with OT at various doses (0 μM, 5 μM, 50 μM and 500 μM) and time points (0 h, 12 h and 48 h). A total of 52 differential proteins in MIA PaCa-2 cells treated with OT were identified, including 14 phosphorylated proteins. Based on the dynamic expression pattern, these proteins were categorized in three clusters, straight down-regulation (cluster 1, 37% of total proteins), upright \"V\" shape expression pattern (cluster 2, 47.8% total), and downright \"V\" shape pattern (cluster 3, 15.2% total). Among them, Annexin A1 expression was significantly down-regulated by OT treatment in time-dependent manner, while no change of this protein was observed in OT dose-dependent fashion. Pathway analysis suggested that inhibition of transketolase resulted in changes of multiple cellular signaling pathways associated with cell apoptosis. The temporal expression patterns of proteins revealed that OT altered dynamics of protein expression in time-dependent fashion by suppressing phosphor kinase expression, resulting in cancer cell apoptosis. Results from this study suggest that interference of single metabolic enzyme activity altered multiple cellular signaling pathways.

Endoscopic ultrasonography (EUS) has evolved into a useful therapeutic tool for treating a broad range of tumors since being introduced into clinical practice as a diagnostic modality nearly three decades ago. In particular, EUS-guided fine-needle injection has proven a successful minimally invasive approach for treating benign lesions such as pancreatic cysts, relieving pancreatic pain through celiac plexus neurolysis, and controlling local tumor growth of unresectable malignancies by direct delivery of anti-tumor agents. One such ablative agent, ethanol, is capable of safely ablating solid or cystic lesions in hepatic tissues via percutaneous injection. Recent research and clinical interest has focused on the promise of EUS-guided ethanol ablation as a safe and effective method for treating pancreatic tumor patients with small lesions or who are poor operative candidates. Although it is not likely to replace radical resection of localized lesions or systemic treatment of metastatic tumors in all patients, EUS-guided ablation is an ideal method for patients who refuse or are not eligible for surgery. Moreover, this treatment modality may play an active role in the development of future pancreatic tumor treatments. This article reviews the most recent clinical applications of EUS-guided ethanol ablation in humans for treating pancreatic cystic tumors, pancreatic neuroendocrine tumors, and metastatic lesions.